Benatar Michael, Staffaroni Adam M, Wuu Joanne, McDermott Michael P, Quintana Melanie, Swidler Jean, Andersen Gail, Huey Edward D, Turner Martin R, Macklin Eric A, Berry James D, McMillan Corey T, Gendron Tania, Onyike Chiadi, Rosen Howard, Heuer Hilary W, Grignon Anne-Laure, Dave Kuldip D, Balas Calaneet, Gleixner Amanda, Satlin Andrew, Dunn Billy, Dacks Penny, Boxer Adam L
Department of Neurology and the ALS Center, Miller School of Medicine, University of Miami, Miami, FL 33129, USA.
Department of Neurology, University of California San Francisco, CA 94158, USA.
Brain. 2025 Aug 5. doi: 10.1093/brain/awaf290.
The idea that it might be possible to prevent some forms of amyotrophic lateral sclerosis and frontotemporal dementia has finally come of age. The hexanucleotide repeat expansion in the C9orf72 gene accounts for ∼10% of all amyotrophic lateral sclerosis and 10-15% of all frontotemporal dementia diagnoses, with the two clinical syndromes co-manifesting in a significant number of patients. As a result, clinically unaffected carriers of pathogenic C9orf72 repeat expansions are currently the largest identifiable population at significantly elevated risk for both amyotrophic lateral sclerosis and frontotemporal dementia, and in whom it might be possible to prevent the emergence of clinically manifest disease. Strategies for the design of disease prevention trials among clinically unaffected C9orf72 carriers have begun to emerge separately in the amyotrophic lateral sclerosis and frontotemporal dementia fields. However, recognition of the need to define neurodegenerative diseases based on biology underscores the need to consider all potential clinical manifestations of a C9orf72 repeat expansion together, rather than the traditional siloed approach of focusing on only amyotrophic lateral sclerosis or only frontotemporal dementia. Indeed, emerging clinical and biological markers that might be used to quantify pre-symptomatic disease progression and to predict the short-term risk of phenoconversion to clinically manifest disease are shared across the phenotypic spectrum. Given the anticipated progress in the development of therapeutic strategies to target the C9orf72 repeat expansion, and the enthusiasm for prevention trials among the unaffected C9orf72 repeat expansion carrier population, now is the time to begin work on the design of disease prevention trials. To this end, The Association for Frontotemporal Degeneration and the ALS Association supported a multi-stakeholder workshop (in Washington D.C., June 2024) to unify efforts to design a prevention trial for the population at elevated genetic risk for the phenotypic spectrum of C9orf72 disease. Here we describe recommendations emanating from this Workshop for the selection of outcome measures, delineation of eligibility criteria, optimal use of biomarkers and digital health technologies, potential analytic frameworks, and relevant regulatory considerations related to C9orf72 disease prevention trials. We also emphasize the importance of the amyotrophic lateral sclerosis and frontotemporal dementia communities working together in partnership with the C9orf72 repeat expansion carrier community, the regulatory authorities, and the broader drug development community.
预防某些形式的肌萎缩侧索硬化症和额颞叶痴呆症或许可行，这一想法终于成熟了。C9orf72基因中的六核苷酸重复扩增占所有肌萎缩侧索硬化症病例的约10%，以及所有额颞叶痴呆症诊断病例的10 - 15%，这两种临床综合征在相当数量的患者中共同显现。因此，携带致病性C9orf72重复扩增但临床未受影响的人群，目前是可识别的最大群体，他们患肌萎缩侧索硬化症和额颞叶痴呆症的风险显著升高，有可能预防临床显性疾病的出现。针对临床未受影响的C9orf72携带者设计疾病预防试验的策略，已分别在肌萎缩侧索硬化症和额颞叶痴呆症领域开始出现。然而，认识到需要基于生物学来定义神经退行性疾病，这凸显了有必要综合考虑C9orf72重复扩增的所有潜在临床表现，而不是传统的孤立方法，即只关注肌萎缩侧索硬化症或只关注额颞叶痴呆症。事实上，新兴的临床和生物学标志物可用于量化症状前疾病进展，并预测向临床显性疾病表型转化的短期风险，这些标志物在整个表型范围内是共有的。鉴于针对C9orf72重复扩增开发治疗策略的预期进展，以及未受影响的C9orf72重复扩增携带者群体对预防试验的热情，现在是时候开始着手设计疾病预防试验了。为此，额颞叶变性协会和肌萎缩侧索硬化症协会支持了一次多方利益相关者研讨会（2024年6月于华盛顿特区），以统一各方努力，为处于C9orf72疾病表型谱遗传高风险的人群设计一项预防试验。在此，我们描述了本次研讨会针对结局指标的选择、纳入标准的界定、生物标志物和数字健康技术的最佳使用、潜在分析框架以及与C9orf72疾病预防试验相关的监管考量所提出的建议。我们还强调了肌萎缩侧索硬化症和额颞叶痴呆症群体与C9orf72重复扩增携带者群体、监管机构以及更广泛的药物研发群体合作的重要性。
